Methamphetamine (METH) is a highly addictive stimulant and acute exposure causes dopamine (DA) release and stimulates midbrain reward centers. In humans, long-term METH exposure leads to DA reductions, which may contribute to drug craving, anhedonia, and other withdrawal symptoms common during METH abstinence. One therapeutic strategy is to develop and test compounds that normalize (increase) DA to determine if treatment with these drugs reduces METH use. In an effort to identify a dopamine transporter (DAT) selective inhibitor, a number of 3-phenyltropane analogs were synthesized by RTI International. Among these, preclinical studies have shown that RTI-336 produced cocaine-like discriminative stimulus effects and reduced cocaine self-administration in rats, and produced dose-dependent suppression of cocaine self-administration in rhesus monkeys. RTI-336 recently received IND-approval (75,778) for preliminary safety testing in healthy male volunteers, and is scheduled to be completed by February 2009. Subsequent to this effort, RTI-336 will be evaluated in a phase I trial involving cocaine-dependent volunteers. The current application puts forth, for the first time, a proposal to evaluate the preliminary efficacy of this very promising candidate medication in non-treatment-seeking METH-dependent volunteers. The following Specific Aims are proposed: 1. To establish dose-effect relationships for the ability of oral RTI-336 (1, 12 or 20 mg) as compared to placebo, to attenuate METH-induced (0 and 30 mg, IV) positive subjective effects;2. To determine the abuse liability of RTI-336 alone and in combination with METH. The proposed work represents an important research effort with considerable public health significance in that it will evaluate a compound targeted specifically at DAT inhibition for the treatment of METH dependence. The knowledge gained may ultimately support development and implementation of evidence-based treatments for METH dependence, a drug abuse problem with tremendous public health impact. PUBLIC HEALTH RELEVANCE: In humans, long-term methamphetamine exposure leads to dopamine reductions, which may contribute to drug craving, anhedonia, and other withdrawal symptoms common during methamphetamine abstinence. One therapeutic strategy is to develop and test compounds that normalize (increase) dopamine to determine if treatment with these drugs reduces methamphetamine use. The current application puts forth, for the first time, a proposal to evaluate the preliminary efficacy of RTI-336 in non-treatment-seeking METH-dependent volunteers.